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- 1. Pharmacotherapy of Psychotic & Mania disorders Late. BRKM GMC Dimrapal, Jagdalpur
- 2. Psychotic disorder • Psychotic disorder are a group of serious illnesses that affect the mind. • They make it hard for someone to • think clearly, • make good judgments, • respond emotionally, • communicate effectively, • understand reality, and • behave appropriately.
- 3. •When symptoms are severe, people with psychotic disorders have trouble staying in touch with reality and often are unable to handle daily life. •But even severe psychotic disorders usually can be treated.
- 4. Types: Schizophrenia: • People with this illness have changes in behavior and other symptoms--such as delusions and hallucinations -- that last longer than 6 months. • It usually affects them at work or school, as well as their relationships.
- 5. Demographics • Onset and Prevalence of Schizophrenia worldwide • About 1% of the population • Usually develops in early adulthood, but can emerge at any time • Schizophrenia Is Generally Chronic • Most suffer with moderate-to-severe impairment throughout their lives • Life expectancy in persons with schizophrenia is slightly less than average • Schizophrenia Affects Males and Females About Equally • Females tend to have a better long-term prognosis • Onset of schizophrenia differs between males (earlier) and females (later) • Schizophrenia Appears to Have a Strong Genetic Component
- 6. A neurobiological illness that impairs: • Perceptions • Thinking • Language • Emotions • Social interactions
- 7. Positive Symptoms Type I Schizophrenia • Hallucinations • Delusions • Thought Disorder • Paranoia • Ideas of Reference • Loose Associations • Thought Broadcasting • Thought Insertion • Concrete Thinking • Odd Speech • Neologisms • Word Salad • Perseveration • Clang Associations • Echolalia • Odd Behavior • Agitation/Aggression • Catatonia • Regression • Stereotypy
- 8. Schizophrenia • Hallucinations • Auditory • Visual • Delusions: Firm, fixed, false belief • Grandeur • Persecution • Ideas of Reference • Self-accusation • Infidelity • Paranoid
- 9. Meaning of terms • Neologisms: • new words or condensations of words used in an attempt to express a highly complex idea. • Word Salad: • an incoherent mixture of words & phrases • Perseveration: • pathological repetition of the same response to different questions. • Clang Associations: • using words similar in sound, but not in meaning. • Echolalia: • repeating of words or phrases of one person by another.
- 10. Cont.. • Agitation/Aggression: constant movement, irritability, confrontation • Catatonia: motor abnormalities • Catalepsy: constantly maintained immobile position • Excited: agitated purposeless motor activity w/o cause • Stupor: marked slowed activity - immobile - unaware • Rigidity: rigid posture - resists all attempts to be moved • Posturing: voluntary assumption of position - long periods • Cerea flexibilitas: person can be molded into position • Negativism: motiveless resistance to all attempts to move • Regression: may assume and maintain fetal position • Stereotypy: repetitive fixed pattern of physical action or speech
- 11. Negative Symptoms Type II Schizophrenia • Flat, Blunt, or Restricted Affect: lack vocal inflection, paucity of expressive gestures, poor eye contact, decreased movement, or unchanging facial expression. • Alogia: poverty of speech • A sociality: lack of social interaction • Anhedonia: lack of interest in activities that formerly brought pleasure • Avolition: lack of goal directed motivation • Inattention: inwardly focused - not aware of surroundings or activity
- 12. Schizoaffective disorder • Has symptoms of both Schizophrenia and a major mood disorder at the same time. • Patients with Schizoaffective Disorder experience a combination of symptoms associated with both diseases, but do not meet the full criteria for either. • Two types of Schizoaffective disorder: • Bipolar type is where the patient has symptoms of a Manic or • Mixed and/or a Depressive episode with his/her psychotic sx.
- 13. Cont… • Depressive type is where the patient has only the symptoms of a Major Depressive Disorder with his/her psychotic symptoms. • Symptoms include: • auditory/visual hallucinations, • suspiciousness, • unusual thought content, • disorganization, • emotional withdrawal, • blunted affect, • inability to express pleasure, and • attention difficulties
- 14. • Schizophreniform disorder: • This includes symptoms of schizophrenia, but the symptoms last for a shorter time: between 1 and 6 months. • Brief psychotic disorder: • People with this illness have a sudden, short period of psychotic behavior, often in response to a very stressful event, such as a death in the family. • Recovery is often quick -- usually less than a month.
- 15. Delusional disorder • Delusional disorder : • The key symptom is having a delusion (a false, fixed belief). • Involving a real-life situation that could be true but isn't, such as being followed, being plotted against, or having a disease. • The delusion lasts for at least 1 month.
- 16. Subtypes: • Erotomanic: someone of higher status loves me • Grandiose: inflated self worth, power, knowledge, identy or special relationship with God or a famous person. • Jealous: belief that one’s sexual partner is unfaithful • Persecutory: belief that you are being wrongly treated in some way - often take their complaints to legal authorities • Somatic: belief that you have some physical defect, disorder, or disease • Unspecified: doesn’t fit any of the above
- 17. • Shared psychotic disorder (also called folie à deux): • This illness happens when one person in a relationship has a delusion and the other person in the relationship adopts it, too. • Substance-induced psychotic disorder: • This condition is caused by the use of or withdrawal from drugs, such as hallucinogens and crack cocaine, that cause hallucinations, delusions, or confused speech.
- 18. • Psychotic disorder due to another medical condition: • Hallucinations, delusions, or other symptoms may happen because of another illness that affects brain function, such as a head injury or brain tumor. • Paraphrenia: • This condition has symptoms similar to schizophrenia. • It starts late in life, when people are elderly.
- 19. Dissociative Disorders • Depersonalization Disorder • Dissociative Amnesia • Dissociative Fugue • Dissociative Identity Disorder (formerly Multiple Personality Disoder)
- 20. Depersonalization • Person feels a change in sense of self - feels mechanical, dreamy, or detached from their body • Temporary state • Usually follows a traumatic event, but is often present during panic attacks
- 21. Dissociative Amnesia • Inability to recall important personal information • Information is frequently traumatic in nature • Sub categories: • Generalized amnesia • Localized amnesia • Selective amnesia
- 22. Dissociative Fugue • Sudden, unexpected travel away from usual surroundings coupled with amnesia of former life • Usually time-limited • Person suddenly remembers who they are and becomes amnesic for the time away • Also follows traumatic event.
- 23. Dissociative Identity Disorder • Splitting of personality into two or more separate and distinct personalities • “Primary” personality usually not consciously aware of others • “Alternates” may be very ill (suicidal) or extremely different from the primary • Caused by extreme trauma in childhood
- 24. Symptoms • Hallucinations means seeing, hearing, or feeling things that don’t exist. • For instance, someone might see things that aren't there, hear voices, smell odors, have a "funny" taste in their mouth, or feel sensations on their skin even though nothing is touching their body.
- 25. • Delusions are false beliefs that don’t go away after even after they've been shown to be false. • For example, a person who is certain his or her food is poisoned, even if someone has shown them that the food is fine, has a delusion.
- 26. Other possible symptoms: • Disorganized or incoherent speech • Confused thinking • Strange, possibly dangerous behaviour • Slowed or unusual movements • Loss of interest in personal hygiene • Loss of interest in activities • Problems at school or work and with relationships • Cold, detached manner with the inability to express emotion • Mood swings or other mood symptoms, such as depression or mania
- 27. Causes • Unknown • Hereditary • Stress induced • Drug abuse • Eventful Life events
- 28. Schizophrenia • May associated with involvement of pathology of some parts of the brain that control thinking, perception, and motivation. • It is also believe that; In schizophrenia, nerve cell receptors that work with a brain chemical called glutamate may not work properly in specific brain regions. • These conditions usually first appear when a person is in his or her late teens, 20s, or 30s. They tend to affect men and women about equally.
- 29. Diagnosis •By: • Medical and psychiatric history • Brief physical exam. • MRI scans
- 30. Management • The antipsychotic drugs are broadly defined as the drugs, which are used to treat the psychiatric disorders. • In earlier times, these drugs were also known as major tranquilizers due to their calming effect; but this term has been abandoned now. • These drugs are also called as neuroleptic agents as they reduce the agitation and disturbed behaviour associated with delusions and hallucinations in schizophrenia (antipsychotic effect) as well as produce a high incidence of extrapyramidal side effects (EPS) at clinically effective doses.
- 31. • The probable cause of mental illnesses involving mania and schizophernia is dopaminergic overactivity in the limbic system, whereas, depression involves monoaminergic (NA, 5-HT) deficiency. • The “atypical” antipsychotic drugs are most widely used nowadays due to their better antipsychotic and minimal extrapyramidal side effect profile.
- 32. The antipsychotic or neuroleptic drugs are classified as: A. TYPICAL ANTIPSYCHOTIC DRUGS SN CLASS DRUGS 1 Phenothiazines Chlorpromazine (CPZ), Triflupromazine, Thioridazine, Trifluoperazine, Fluphenazine 2 Butyrophenones Haloperidol, Trifluperidol, Penfluridol 3 Thioxanthenes Flupenthixol 4 Other heterocyclics Pimozide, Loxapine A. ATYPICAL ANTIPSYCHOTICS Clozapine, Risperidone, Olanzapine, Quetiapine, Aripiprazole, Ziprasidone, Amisulpiride, Zotepine
- 33. MECHANISM OF ACTION OF ANTIPSYCHOTIC DRUGS • All antipsychotics (except atypical antipsychotics) have common mechanism of action. • These drugs have potent dopaminergic D2 receptor blocking action in the ‘limbic system’ and in mesocortical region, which is responsible for their antipsychotic action. • The atypical antipsychotic drugs block dopaminergic as well as other monoamine receptors especially 5HT2A.
- 34. PHARMACOLOGICAL EFFECTS OF CHLORPROMAZINE (prototype) SITE EFFECTS CNS (by blocking Dopaminergic receptors) a. Limbic system a. Decrease in spontaneous motor activity, induction of sleep and improvement of cognitive & intellectual function. a. Mesocortical area a. Basal ganglia a. Extrapyramidal symptoms, reduces spasticity. a. Pituitary a. Prolactin release (gynaecomastia in male; galactorrhoea in females) a. CTZ a. Antiemetic effects CVS (α1 adrenergic receptor) • Postural hypotension, tachycardia, palpitations and Q-Tc prolongation (at higher doses). Skin (H1 receptor) • Antipruritic effects GIT (M3 receptor) • Dry mouth, constipation Eye (M3 receptor) • Blurred vision Urinary bladder (M3 receptor) • Urinary retention
- 35. Pharmacokinetics • Antipsychotic drugs are erratically absorbed from the GIT; whereas, intramuscular and intravenous doses produce consistent effects. • These drugs are widely distributed in the tissues and often accumulate after repeated administrations. • These drugs crosses BBB and attain higher concentrations in brain than in plasma. • These drugs cross placental barrier and also enter the breast milk.
- 36. Cont… • They are metabolized in the liver and excreted through the bile and urine with an average t1/2 of 18- 30 hours. • The excretion remains continued for months even after discontinuation of the drug due to cumulative effect. • The dose adjustment of antipsychotic drugs is advocated according to age as metabolism of these drugs is faster in children & slow in elderly individuals. • The patients should be informed/counseled regarding long duration of treatment as the clinical effects of these drugs appear after few weeks only.
- 37. Drug Dose (mg/day) Common pharmacological effects Special features Extrapyramidal Sedative Hypotension TYPICAL ANTIPSYCHOTICS DRUGS Triflupromazine 50–200 High High Moderate More potent than CPZ. Used as antiemetic. On IV injection, its produces acute muscle dystonias (especially in children). Thioridazine 100–400 Very low High High Has marked central anticholinergic action. Cardio-toxic & causes inhibition of ejaculation. It also damages eye; hence long-term therapy should be avoided. Trifluoperazine 2–20 High Low Low They have minimum autonomic actions. The incidence of loss of glycemic control, hepatotoxicity and hypersensitivity reactions are little. Fluphenazine 1–10 Haloperidol 2–20 High Low Low It is a potent antipsychotic. Used in acute schizophrenia, Huntington’s disease & Gilles de la Tourette’s syndrome. Fewer incidences of seizure, weight gain and hepatotoxicity.
- 38. Drug Dose (mg/day) Common pharmacological effects Special features Extrapyramidal Sedative Hypotension TYPICAL ANTIPSYCHOTICS DRUGS Flupentixol 3–15 High Low Low Less sedative than CPZ. Used in schizophrenia and other psychotic disorders such as in withdrawn and apathetic patients. Rarely used nowadays. Pimozide 2–6 High Low Low Selective DA antagonist with little α-adrenergic or cholinergic blocking activity. Used for the treatment of Gilles de la Tourett’s syndrome and in ticks. It has long duration of action; hence, used for maintenance therapy. Causes cardiac arrhythmia as a side effect. Loxapine 20–50 Moderate Low Moderate It is shortest and fastest acting antipsychotic drug.
- 39. ATYPICAL ANTIPSYCHOTICS DRUGS (Clozapine, Risperidone, Olanzapine, Quetiapine, Aripiprazole, Ziprasidone, Amisulpiride, Zotepine)
- 40. •These are also called 2nd generation antipsychotic drugs. •They differ from typical or classic antipsychotic drugs as follows: •They have weak D2 receptor blocking activity along with potent 5-HT2 antagonistic activity.
- 41. • The antipsychotic effect is attributed to a combination of dopaminergic and 5-HT2 receptor blockade. • They are effective in the patients refractory to typical antipsychotic drugs. • The incidence of extrapyramidal side effects is very low than typical antipsychotics as their affinity towards D1 and D2 receptors is very low.
- 42. Clozapine It is the first atypical antipsychotic. It blocks D1, D4, 5-HT2, α-adrenergic & H1receptor with relatively weak D2 selectivity. Most effective in Both positive and negative symptoms of schizophrenia Refractory schizophrenia. Low sedation and low incidence of EPS is there. Dose (mg/day) Common side effects Extra pyramidal Sedation Hypotension 100–300 No High High
- 43. The common side effects are weight gain, hyperlipidemia, loss of glycemic control, seizure (in high dose), tachycardia and urinary incontinence. It causes agranulocytosis and other blood dyscrasias: hence, weekly monitoring of leucocyte count is advocated.
- 44. Risperidone • D2 + 5-HT2 receptor antagonist with high affinity for α1, α2 and H1 receptors. • More potent than clozapine. • Weight gain & the incidence of diabetes is less prominent than clozapine. • It increases the level of prolactin. • It may produce EPS at high dose. • Should be avoided in elderly patients with stroke. Dose Extrapyramidal Sedation Hypotension 2–8 Moderate Moderate Moderate
- 45. Olanzapine • Blocks D2, 5-HT2, α1, α2, H1 and muscarinic receptors. • Used for both positive and negative symptoms of schizophrenia and mania. • The common side effects are • weight gain, • loss of diabetic control and • increase incidence of seizure. Dose Extrapyramidal Sedation Hypotension 2.5–20 Low Low Moderate
- 46. Quetiapine • Short-acting atypical antipsychotic. • It blocks the 5-HT1A, 5-HT2, D2, α1 , α2 and H1 receptors in the brain. • Used in mania and bipolar depressive disorder as maintenance therapy. • Not effective in schizophrenia. • S/E: Weight gain and loss of diabetic control with QT prolongation. Dose Extrapyramidal Sedation Hypotension 50–400 Very low High Moderate
- 47. Aripiprazole • It is partial agonist at D2, 5-HT1A with 5-HT2 receptors antagonist. • Used in schizophrenia, mania and bipolar disorders. • The common side effects are • nausea, • dyspepsia, • constipation, • light-headedness and • prolongation of Q-Tc (at higher doses). Dose Extrapyramidal Sedation Hypotension 5–30 Very low Very low Very low
- 48. Ziprasidone • It blocks D2 + 5-HT2A/2C+ H1+ α1 for antipsychotic action. • It also blocks the 5-HT1D and agonist at 5-HT1A receptors with inhibition of 5-HT and NA reuptake resulting its antianxiety & antidepressant actions. • The common side effects are • nausea, • vomiting and • dose related prolongations of Q-Tc. Dose Extrapyramidal Sedation Hypotension 40–160 Low Low Low
- 49. Amisulpiride • It has high affinity for D2& D3 and has low-affinity for 5-HT2 receptors. • Used in the treatment for negative symptoms associated with schizophrenia. • The common side effects are • anxiety, • insomnia, • agitation, • Q-Tc (in elderly) and • hyperprolactinemia. • It has low incidence of weight gain. • Dose: • schizophrenia 50–300 mg/day BD • acute psychosis 200–400 mg BD. Extrapyramidal Sedation Hypotension Low No Low
- 50. Zotepine • DOES: 25-100mg TDS • Blocks D2+D1, 5-HT2, α1, H1 receptors and NA reuptake. • Used for positive and negative symptoms of schizophrenia. • The common side effects are • headache, • postural hypotension, • weight gain, • hyperglycaemia and • dyslipidemia. Dose Extrapyramidal Sedation Hypotension 25-100mg TDS Low Low Low
- 51. Lurasidone It is a novel 5-HT/DA antagonist. It possesses potent activity at 5-HT7 receptor sites, actions that, based on preclinical and early clinical studies, may be associated with cognitive benefits. It is devoid of most of the side effects associated with atypical antipsychotics.
- 52. COMMON INDICATIONS OF ANTIPSYCHOTIC/ NEUROLEPTIC DRUGS • Psychiatric illness • Schizophrenia • Control of acute mania and also for long term treatment. • Organic brain syndromes (dementia and delirium). • Anxiety (BZDs preferred). • Neuro-psychiatric illness • Alcoholic hallucinations. • Huntington’s disease. • Gilles de la Tourette’s.
- 53. Indications • Non-psychiatric illness • As antiemetic (at doses much lower than needed as antipsychotic). • Intractable hiccough (parenteral chlorpromazine is used). • As preanaesthetic medication (promethazine).
- 54. COMMON SIDE EFFECTS OF ANTIPSYCHOTIC/NEUROLEPTIC DRUGS System Adverse effects CNS Drowsiness, lethargy, mental confusion and agitation, extrapyramidal side effects CVS Postural hypotension, palpitations, Q-Tc prolongation and cardiac arrhythmias. Endocrine Hyperprolactinemia. Amenorrhoea, infertility, galactorrhoea in females and gynaecomastia in males also occur, but infrequently after prolonged treatment. Metabolic Increase in appetite, weight gain, loss of diabetic control and dyslipidemia. Eye Blurring of vision GIT Constipation, dry mouth. Urinary system Urinary hesitancy in elderly males
- 55. Extrapyramidal side effects (EPS) • The extrapyramidal side effects are mostly seen with potent typical antipsychotic drugs and rarely with atypical antipsychotics. • Parkinsonism, • Acute muscular dystonias, • Akathisia and • Malignant neuroleptic syndrome appear early during the treatment, whereas • Rabbit syndrome and Tardive dyskinesia appear nearly a year after initiating the treatment.
- 56. Parkinsonism • Features; • Presents as rigidity, tremors, hypokinesia, mask like facies, shuffling gait. • Appears between 1–4 weeks of therapy and persists unless dose is reduced. • Perioral tremors ‘rabbit syndrome’ seen after a few years of therapy. • Management: • Changing from typical to atypical antipsychotic reduces these symptoms. • Central anticholinergic drugs are used treat Perioral tremors.
- 57. Acute muscular dystonias • Features • Presents as muscle spasms with involvement of linguo-facial muscles (tongue thrusting, torticollis, locked jaw are seen). • It occurs within a few hours of a single dose or within first week of therapy. • Most common seen in children ≤10 years and in girls, particularly after parenteral administration. • Management: • Central anticholinergics, promethazine or hydroxyzine injected IM, provide relief within 10–15 min.
- 58. Akathisia • Features: • It is the most common extrapyramidal side effects of antipsychotic medications. • Patient presents as feeling of discomfort, restlessness and agitation • It occurs between 1–8 weeks of therapy. • Management: • Changing of antipsychotic from typical to atypical reduces these symptoms. • Benzodiazepine like clonazepam or diazepam is used as first choice of treatment. • In non-responsive individuals, propranolol is used.
- 59. Malignant neuroleptic syndrome • Features: • It is rare condition and seen at higher dose of potent typical antipsychotics. • It presents as marked rigidity, immobility, tremor, hyperthermia, semi-consciousness, fluctuating BP and heart rate. • It is a fatal condition; death occurs due to cardio- pulmonary collapse. • Management: • Symptomatic management is advocated first. • Intravenous dantrolene may benefit. • Bromocriptine in large doses has been found useful
- 60. Tardive dyskinesia • Features: • It presents as purposeless involuntary facial and limb movements such as chewing, puffing of cheeks and choreoathetoid movements. • It is more common in elderly women • Management: • Changing of antipsychotic from typical to atypical ones may reduce these symptoms.
- 61. Comparative adverse effects profile of atypical antipsychotic drugs Drugs Weight Gain Hyper- lipidemia New-Onset Diabetes Mellitus QTc Prolongation Clozapine High High High Negligible Risperidone Moderate Moderate Moderate Low Olanzapine High High High Negligible Quetiapine Moderate Moderate Moderate High Aripiprazole Negligible No No Moderate Ziprasidone Negligible No No High Lurasidone No No No No
- 62. Schizophrenia related symptoms Drug therapy Agitated, combative and violent Haloperidol, Quetiapine, CPZ, Thioridazine. Withdrawn and apathetic Trifluoperazine, Fluphenazine, Aripiprazole, Ziprasidone. Patient with mainly negative symptoms and resistant cases Clozapine Is The Most Effective; Alternatives Are: Olanzapine, Risperidone, Aripiprazole, Ziprasidone. Patient with mood elevation, hypomania Haloperidol, Fluphenazine, Quetiapine, Olanzapine. If extrapyramidal side effects must be avoided Thioridazine, Clozapine Or Any Other Atypical Antipsychotic. Elderly patients who are more prone to sedation, mental confusion and hypotension Phenothiazine, Haloperidol Or Aripiprazole.
- 63. Mania
- 64. • Bipolar disorder is a complex disorder that likely stems from a combination of genetic and non- genetic factors. • The mood episodes associated with it involve clinical depression or mania (extreme elation and high energy) with periods of normal mood and energy in between episodes. • The severity of mood episodes can range from very mild to extreme, and they can happen gradually or suddenly within a timeframe of days to weeks.
- 65. • When discrete mood episodes happen four or more times per year, the process is called rapid cycling. • Rapid cycling should not be confused with very frequent moment-to-moment changes in mood, which can sometimes occur in people with bipolar disorder or other conditions such as borderline personality disorder.
- 67. • Bipolar disorder usually appears between ages 15 and 24 and persists through a lifetime. • It's rare that newly diagnosed mania is seen in young children or in adults over age 65. • It is marked by relapses and remissions, bipolar disorder has a high rate of recurrence if untreated.
- 68. • Patients with severe mania usually require hospitalization to keep them from risky behaviors. • Those who are severely depressed also might need hospitalization to keep them from acting on • suicidal thoughts or • psychotic symptoms (delusions, hallucinations, disorganized thinking).
- 69. Symptoms of Bipolar Disorder • Decreased appetite/ weight loss, or overeating/ weight gain • Difficulty concentrating, remembering, and making decisions • Feelings of guilt, • Insomnia • Lack of interest • Persistently sad, anxious, or "empty" moods • Restlessness, irritability • Suicide attempts
- 70. Signs of Mania • Disconnected and very fast (racing) thoughts • Grandiose beliefs • Inappropriate elation or euphoria • Inappropriate irritability • Inappropriate social behaviour • Increased sexual desire • Increased talking speed or volume • Markedly increased energy • Poor judgment • A decreased need for sleep due to high energy
- 71. Diagnosis • Clinically • Mania • Hypomania • Depression • Dysthymia
- 72. Management
- 73. MOOD STABILIZERS • Mood stabilizers are the drugs that are used to control the mood swings. • Mood swings are oftenly seen in bipolar mood disorder. • These drugs are also known as anti-manic drugs. • Bipolar disorder is a psychiatric illness, which is characterized by a period of depression followed by a period of mania.
- 74. • The cause of mania is not understood, but it is thought to be due to overstimulation of certain neurons in the brain that manifests as hyperactivity, agitation, uncontrolled thought and speech disorder etc. • The mainstay for treatment of mania has always been lithium.
- 75. •Nowadays, many other drugs are also used for the treatment of bipolar disorders, which includes • Antipsychotic drugs such as: • Aripiprazole, • Olanzapine, • Quetiapine, • Ziprasidone • Antiepileptic drugs such as • lamotrigine
- 76. Lithium • Lithium was first used in patients with gout in 19th century. • In 1949, Cade discovered that lithium was an effective treatment for bipolar disorders. • It reduces episodes and phases of manic- depressive disorder by reduction of mood swings, motor activity of brain, euphoria and insomnia.
- 77. Mechanism of action • The exact mechanism is still unknown. • It is a monovalent cation which mimics the role of sodium ions at many sites. • The proposed hypothesis is as follows: • Lithium competes and replaces sodium at many sites including neurons. It alters sodium transport in nerve and muscle cells and results in mood stabilizing effects. • It also inhibits the release of norepinephrine and dopamine, but not serotonin, from stimulated neurons. • It increases the intraneuronal stores of norepinephrine and dopamine slightly; and decreases intraneuronal content of second messengers. • It selectively modulates the responsiveness of hyperactive neurons that might contribute to the manic state.
- 79. Pharmacokinetics • The oral absorption of lithium is virtually complete within 6–8 hours. • It is not metabolized in the body and handled by the kidneys in the same way as sodium ions. • Lithium is excreted from the kidneys within 10-12 hours, although about 80% is reabsorbed. • The plasma t ½ is 20 hours.
- 80. PK • It slowly crosses the blood–brain barrier. • It also crosses the placenta & enters breast milk; hence contraindicated in pregnancy and lactation. • Sodium depletion reduces the rate excretion of lithium, thus increases the lithium toxicity. Therefore, patients must be encouraged to maintain hydration while taking this drug. • It has low therapeutic index; therefore, continuous monitoring (by salivary concentration of lithium) is required for optimal therapy.
- 81. Dose • Initial dose: 600 mg/day followed by 600–1200 mg/day till the optimal therapeutic concentration achieved. • The therapeutically effective serum level is 0.6 to 1.2 mEq/L (0.5-1.5 mmol/L).
- 82. Indications • Prophylaxis for bipolar disorder. • Acute mania. • Chemotherapy induced leucopenia. • Syndrome of inappropriate anti-diuretic hormone (SIADH). • Cluster headache.
- 83. Adverse Effects • The side effects of lithium are directly associated with the serum levels of drug. • Serum levels of <1.5 mEq/L: • CNS problems, including lethargy, slurred speech, muscle weakness, and fine tremor; • polyuria, which relates to renal toxicity; • beginning of gastric toxicity, with nausea, vomiting, and diarrhea. • Serum levels of 1.5 to 2 mEq/L: • Intensification of all of the foregoing reactions, with ECG changes.
- 84. Cont… • Serum levels of 2 to 2.5 mEq/L: • Possible progression of CNS effects to ataxia, clonic movements, hyperreflexia, and seizures; • possible CV effects such as severe ECG changes and hypotension; • large output of dilute urine secondary to renal toxicity; • fatalities secondary to pulmonary toxicity. • Serum levels >2.5 mEq/L: • Complex multi-organ toxicity, with a significant risk of death. • Other side effects include hypothyroidism, weight gain, and diabetes insipidus.
- 85. Management of lithium overdose • Lithium should be stopped immediately. • The serum level of lithium should be monitored regularly. • IV administration of normal saline restores sodium levels and promotes lithium excretion. • IV infusion of mannitol increases lithium excretion. • If serum level is > 4 mEq/L; haemodialysis is required. • Other diuretics, which increase sodium loss can cause the reabsorption of lithium from the kidney tubules and enhance the toxicity; hence, contraindicated.
- 86. Problem with lithium • It inhibits the action of ADH on distal tubules in the kidney leads to diabetes insipidus. • Leukocyte count is increased by lithium therapy. • Lithium inhibits release of thyroid hormones resulting in feedback stimulation of thyroid through pituitary leads to hypothyroid. • Tremors • Teratogenicity (Ebstein’s anomaly) • Polyuria
- 88. Sodium valproate • It reduces the manic relapses in bipolar disorder. • It is now a first line treatment of acute mania in which high dose valproate acts faster than lithium and is an alternative to antipsychotic ± benzodiazepine. • It can be useful in those not responding to lithium or not tolerating it. • Patients with rapid cycling pattern may particularly benefit from valproate therapy.
- 89. Sodium valproate • Combination of lithium and valproate useful in resistant cases. • It is also used as prophylaxis in bipolar disorder. • Combination of valproate with an atypical antipsychotic has high efficacy in acute mania. • Divalproex, a compound of valproate, is more commonly used due to better gastric tolerance.
- 90. Carbamazepine • Carbamazepine (CBZ) was found to prolong remission in bipolar disorder. • Carbamazepine is less effective than lithium or valproate in acute mania. • High dose require for controlling rapid cycle. • Produces in long term therapy- neurotoxicity and increases suicides tendency
- 91. Lamotrigine • It is a newer anticonvulsant for prophylaxis of depression in bipolar disorder. • Lamotrigine is not effective for treatment as well as prevention of mania. • It is used for maintenance therapy of type II bipolar disorder because it reduces the risk of mania. • Lamotrigine can be combined with lithium to improve its efficacy.
- 92. Atypical antipsychotics Olanzapine, risperidone, aripiprazole, quetiapine, with or without a BZD. • These are the first line drugs for control of acute mania. • But in severe cases, requiring urgent parenteral therapy, for which the older neuroleptics are still the most effective.
- 93. • Aripiprazole • Used for the treatment of mania in bipolar I disorder, both as monotherapy as well as adjuvant to lithium or valproate. • Maintenance therapy with aripiprazole prevents mania, but not depressive episodes. • Olanzapine • Used for maintenance therapy of bipolar disorder. • It improves both manic and depressive phases. • Not used as long-term therapy due to higher risk of weight gain, hyperglycaemia.
- 94. • Quetiapine • Used with combination of an atypical antipsychotic with valproate or lithium. • Mainly indicated in maintenance therapy of bipolar disorder.